Protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs) are key enzymes in signal-transduction pathways for a wide range of cellular processes. PTKs and PTPs are highly expressed in the central nervous system, which is consistent with the importance of tyrosine phosphorylation in neuronal function. Protein phosphorylation is known to be involved in the regulation of neurotransmitter receptors, but the effects of tyrosine phosphorylation on neurotransmitter receptor function in the central nervous system are unknown. Here we present evidence that in mammalian central neurons tyrosine phosphorylation regulates the function of the NMDA (N-methyl-D-aspartate) receptor, a subtype of excitatory amino-acid receptor. NMDA-receptor-mediated whole-cell currents and intracellular Ca2+ responses are depressed by inhibition of PTKs. Conversely, NMDA currents are potentiated by intracellular application of the well characterized PTK pp60c-src. NMDA currents are also potentiated by intracellular administration of an inhibitor of PTPs. Protein-tyrosine phosphorylation is a new mechanism for regulating NMDA receptors and may be important in neuronal development, plasticity and toxicity.